Overall - Project Summary Thoracic aortic aneurysms (TAA) are a group of life threatening conditions for which there is no good therapy. We have proposed that specific genetic defects and environmental insults that alter distinct aspects of the physiological interactions amongst cells and ECM lead to TAAs. As such, we view TAA as a disease of altered vascular mechanobiology. In this Program Project Grant application, we will focus on the biological responses of aortic cells, namely smooth muscle cells (SMC) and endothelial cells (EC) to the two major physical determinants of disease, namely decreased ECM integrity and increased hemodynamic loads. We will examine responses of ECs and SMCs during aneurysm development in mice with normal or compromised ECM while focusing on signaling through angiotensin II and transforming growth factor beta in response to increased hemodynamic loads. We will examine responses of the multiple mouse models to changes in flow, pressure, and additional genetic perturbations focusing on AT1r, TGFBR1/2, TGF?, and flow-dependent signaling and activation (e.g., VECAD and PECAM). Consequences of cellular and tissue changes will be analyzed with our Computational and Experimental Biomechanical Assessment and Bioinformatics and Modeling Cores. For example, a subset of mice from all mouse models will be tested in the Computational and Experimental Biomechanical Assessment core for biomechanical parameters and all differentially expressed gene data from RNAseq experiments will be analyzed in the Bioinformatics and Modeling core. In this way the information from all four projects can be applied en mass yielding considerably more significance. Our intent is to develop novel interpretations from the changes in biomechanics and cell signaling to yield new testable hypothesis concerning ECM modulation in addition to the revelation of important signaling nodes and novel potential drug therapies. We propose that a consistent, integrated approach, using unique but complementary mouse models for aneurysm genesis and progression, studied under several conditions will yield unique insights in a synergistic manner.